MX2007002462A

MX2007002462A - Methods for transmembrane treatment and prevention of otitis media.

Info

Publication number: MX2007002462A
Application number: MX2007002462A
Authority: MX
Inventors: William R Campbell
Original assignee: Piedmont Pharmaceuticals Llc
Priority date: 2004-09-03
Filing date: 2005-09-02
Publication date: 2007-10-10
Also published as: EP1784164A4; WO2006029074A3; CA2579805A1; BRPI0514898A; EP1784164A2; JP2008512383A; AU2005282571A1; US20080124385A1; WO2006029074A2

Abstract

Methods for treating and preventing middle ear infections by transmembrane administration of medicament-containing transmembrane carrier compositions, such as liposomes and other lipid vesicles, to the tympanic membrane. Medicaments useful for treating pain, inflammation or infection in the outer ear may be co-administered. If utilized for transmembrane administration, the liposomes or other lipid vesicles will usually not be sterically stabilized. The medicaments delivered according to the methods of the invention include antibiotic, anti-viral, anti-fungal and anti-inflammatory agents that are useful in treatment and/or prophylaxis of middle ear infections and their sequelae.

Description

METHODS FOR THE TREATMENT OF TRANSMEMBRANE AND PREVENTION OF MEDIUM OTITIS FIELD OF THE INVENTION The present invention relates to non-invasive methods for the treatment of otitis media (infection of the middle ear). More particularly, the invention relates to methods for administering medicament useful in the treatment of otitis media for the middle ear by releasing it through the tympanic membrane (eardrum).

BACKGROUND OF THE INVENTION Millions of children are affected each year with otitis media, that is, middle ear infection. Although adults are also susceptible to middle ear infections, children are particularly at risk because their relatively short channels can be closed more easily by inflammation. The fluid can then be trapped behind the tympanic membrane (eardrum), which can cause severe pain as well as provide microbes with an attractive environment in which they reproduce.

The tympanic membrane is a formidable barrier against the introduction of drugs in the middle ear and so the antibiotics described to treat middle ear infections are almost always taken orally. However, a variety of bacteria and viruses can be responsible for causing infections in the middle ear and it is not often possible to distinguish which is the cause of a particular infection or if it is susceptible to treatment with oral antibiotics. In addition, the impact of administering antibiotics orally in the middle ear can be diluted by the systemic distribution of the drug that can also place the patient at risk of side effects associated with systemic release (ie, yeast infections in female patients).

Children who suffer from repeated infections may require surgery to relieve fluid pressure in the tympanic membrane. In the most severe cases, the drainage tubes can be placed inside the tympanic membrane. The tubes themselves do not foresee recurrences of the infection (on the contrary, they can serve as conduits for the entry of additional pathogens into the middle ear), but they can relieve the pressure and reduce the extent to which the fluid reaches trapping behind the eardrum. The tubes also offer a potential conduit for antibiotics to enter the middle ear directly, that is, by applying antibiotic drops and allowing them to flow into the drainage tube. However, this method is both invasive and painful, suggesting a strong need for an alternate route to introduce antibiotics into the middle ear.

SUMMARY OF THE INVENTION Surprisingly, it has been found that drugs can be introduced directly into the middle ear by transmembrane release. According to the invention, the medicament is supplied as an active ingredient of a transmembrane carrier composition applied to the tympanic membrane (tympanic membrane), such as a lipid-based emulsion, lipid vesicle, liposomes, lyosomes, micelles, transferomas and carriers. Polymers capable of releasing an agent through the tympanic membrane.

Preferred embodiments are those useful in the treatment or prevention of otitis media (infection of the middle ear) and its sequelae. The invention is particularly well suited for the delivery of medicaments such as antibiotics or anti-viral agents (depending on the source of infection present), anti-fungal agents and anti-inflammatory agents or other analgesics. For the prevention of chronic recurrent middle ear infections, the methods of the invention can also be used among active infections to deliver the prophylactic agents to the middle ear.

The summary of the invention described above is not limiting and other features and advantages of the invention will be apparent from the detailed description of the preferred embodiments, as well as from the claims.

DETAILED DESCRIPTION OF THE INVENTION A. Methods for the Transmembrane Treatment of Otitis Media The present invention provides methods for treating and preventing otitis media through the administration of medicaments useful in the prophylaxis or treatment of middle ear infections and their sequelae in a composition of the transmembrane carrier. The invention is derived from the surprising discovery that in an appropriate carrier, drugs can be released through the tympanic membrane, without piercing the membrane (i.e., by inserting tubes or injection).

By "transmembrane administration" it is meant that a transmembrane carrier composition of the invention capable of crossing the tympanic membrane is applied on the outer side of the ear of the tympanic membrane to deliver a medicament to the middle ear. In addition, the invention provides methods for preventing and / or treating middle ear infections and their sequelae by transmembrane administration of a drug to the tympanic membrane of the affected individual.

Transmembrane administration is achieved via, for example, applying the composition of the transmembrane carrier of the invention to the tympanic membrane via any medically capable medium of application of a pharmaceutical composition to the tympanic membrane, i.e., by application of the carrier composition to the membrane by inserting a syringe without a needle or dropper into the ear canal. The administration is repeated as required to achieve the therapeutically effective dose level for the given antibiotic compound, for example 5-10 drops of a transmembrane carrier composition consisting of 0.3% in Weight / weight of antibiotic could be released twice a day to treat otitis media in an affected child.

Those skilled in the art will be familiar with and quickly able to select the appropriate dose regimens to continue treating a particular infection. The selected dose regimen will be in accordance with the established clinical protocols for the release and use of the particular carrier and the drugs provided in accordance with the invention. In one embodiment, the medicament is provided in a concentration in a liquid-based carrier of at least about 0.3% weight / weight.

The compositions are preferably administered with the composition of the transmembrane carrier by itself as a carrier, but in various embodiments the transmembrane carrier can be administered in a carrier gel or other suitable carrier.

B. Liquid-Based Carriers for Use in the Invention Although the invention will not be limited by any theory such as the mechanism of action of said release, it is currently believed that an appropriate carrier for the transmembrane release of a medicament is one that is capable of interaction (ie Van der Waals interaction) with and possibly also enters the lipid-rich channels in the tympanic membrane. Here, currently preferred transmembrane carriers are those that are lipid-based, such as lipid emulsions (including microemulsions and oil-in-water emulsions), as well as lipid vesicles). Phospholipid-based formulations are currently preferred, especially for the non-vesicular formulations useful in the invention.

Again without limiting the invention by any theory of its mechanism of action, it is also observed that transmembrane release is more efficient in an acute phase of infection, where the tympanic membrane is inflamed inwardly (ie in the outer ear) due to to the accumulated pressure in the middle ear, a symptomatic mark of acute otitis media infection.

The inflammation indicates that the fluid becomes trapped behind the membrane. The introduction of the lipid-based barriers of the invention on the opposite side of the membrane can create a differential osmotic pressure that facilitates the transmembrane transfer of the drug, from or together with the lipid-based carrier.

More preferably, the transmembrane lipid vesicle compositions are flexible, in that they do not include a steric stabilization component, such as cholesterol (although sterically stable vesicles can be used to co-administer the drugs in the outer ear, as described in additional form later). In addition, the medicament released according to the invention is preferably carried in a lipid phase (ie, in the lipid bilayer of a liposome) rather than in an aqueous phase (i.e., in the center of a liposome). In addition, lipid-soluble medicaments (which can generally be provided in a high concentration in the lipid layer of a vesicle that a water-soluble medicament dispersed in an aqueous phase may be preferred, although they are not required for use in the invention.

Methods for preparing lipid emulsions and vesicles are well known in the art and will only be briefly reported with respect to the currently most preferred embodiment of the composition of the transmembrane carrier for use in the invention, a liposome prepared without a steric stabilizer. and with little or no addition of a viscosity improving agent.

By "liposome" is meant a spherical vesicle joined by an ordered lipid bilayer and closing an aqueous phase. The lipid bilayer of liposomes is usually made from synthetic and natural phospholipids but can also be made from non-phospholipids. The lipid bilayer of liposomes is an ordered bilayer, meaning that the molecular structures "head" and "tail" of the lipids are one line followed by the other.

The liposomes used in the present invention may be unilamellar (having a lipid bilayer) or are preferably multilamellar. Liposomes that are "multilamellar" have multiple layers or membranes. This type of liposome has layers of lipid bilayers with an aqueous fluid spaced between the lipid bilayers. Multilamellar liposomes have at least two layers of lipids.

Preferred liposomes are those described in this document and in co-pending co-dependent US Patent Application Serial No. 10 / 366,584 filed on February 12, 2003, the description of which is incorporated herein. in its entirety as a reference. However, those skilled in the art will recognize that other liposome formulations can be used including phosphatidyl compounds, such as phosphatidylglycerol, phosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, sphingolipids, cerebrosides and gangliosides. Particularly useful are diacylphosphatidylglycerols, wherein the lipid portion contains from 14-18 carbon atoms, particularly from 16-18 carbon atoms, and is saturated. Illustrative phospholipids include egg phosphatidylcholine, dipalmitoylphosphatidylcholine and distearoylphosphatidylcholine. Said lipids are also useful in the compositions of the non-vesicular transmembrane carrier of the invention.

The size of the liposomes and the lipid vesicles used in the present invention, if any, may be variable, but such vesicles are preferred in uniform size in each batch preparation. The liposomes can be more than 20 μm, 25 μm or even 30 μm. But in preferred embodiments about 95% of the liposomes will be from about 0.5 μm to about 10 μm in diameter. In one embodiment, at least 80% of the liposomes in a preferred composition made in accordance with the methods described herein are from about 0.5 μm to about 5 μm. In this respect, the term "approximately" covers a range of 5% ascending or descending the established value. The actual diameters of the liposomes will be a function of the cooling curve followed and the length and vigor of the agitation or vertex hydration, when those processes are used in the manufacture of liposomes. In still other embodiments, the liposomes may be multilamellar liposomes wherein a larger single liposome encapsulates one or more of the smaller liposomes.

Conventional liposomes manufactured in accordance with means well known in the art may be used in the invention, but preferred liposomes of the present invention do not contain a lipid-soluble preservative as found in prior art liposomes (see, for example, US Pat. Nos. 4,761, 288 and 4,897,269, both of Mezei, are both incorporated herein by reference in their entirety). In addition to what is described in co-dependent US Patent Application No. 10/366584 (incorporated herein in its entirety), the liposomes of the present invention use a water soluble condom that can function as an antimicrobial, which preferably it is a benzethonium salt, such as benzethonium chloride.

In this respect, "preservative" refers to an ingredient added to the composition of the transmembrane carrier that prevents microbes from substantial growth and multiplication in the formulation. In addition, by "soluble water" it is meant that the ingredient has an excess water solubility of 100 μg / ml (or 0.01%) in water. In other embodiments, the ingredient may have a solubility in water in excess of 1 mg / ml (0.1%).

However, other water-soluble preservatives will also find use in the invention, such as benzoic acid and benzylconium salts such as benzylconium chloride. It was unexpectedly discovered that condom selection is important to achieve stable liposomes, such as lipid-soluble preservatives that can weaken and destabilize the structure of liposomes due to microbial growth, leading to an unstable composition with low viscosity. Other water-soluble preservatives can be used and are advantageously selected to be active in the pH of the composition.

In a preferred embodiment of the invention, the liposomes used also contain vitamin E as a lipid-soluble antioxidant. Antioxidants act as scavengers of free radicals facilitating the achievement of maximum stability for liposomes. Methylcellulose or other viscosity improving agents are included in the compositions of the transmembrane carrier that are applied to the skin to achieve sufficient viscosity and to avoid a fluid composition. In a more preferred embodiment, the present compositions include vitamin E as an anti-oxidant and include less than 2% w / w or less than 1.5% or less than 1.0% or less than 0.5% or less than 0.25% of an agent Improved viscosity.

More preferably, the compositions do not include any methylcellulose or any other viscosity improving agent, which allows for optimal transmembrane penetration of the active drug compound. In an embodiment of at least 50% of the Vitamin E is present in the lipid bilayers of the liposomes. In other embodiments, at least 70% or 80% or 90% or 95% of vitamin E is present in the lipid layers of liposomes.

By "viscosity improving agents" is meant that an agent is added to the composition to increase the viscosity. A viscosity improving agent will increase the viscosity of the composition by at least 10,000 centipoise at 25 ° C. Viscosity improving agents include but are not limited to methylcellulose, alginic acid, gelatin, acacia sap (Arabica gum) and keto-stearyl alcohol. Phospholipids are not considered to be viscosity-improving agents within this definition. The viscosity improving agent will increase the viscosity by at least 10,000 centipoise against its absence and in other embodiments it can increase the viscosity by 20,000 or 30,000 centipoise (as high as 40,000 or 50,000 centipoise) against its absence in the composition.

In addition in various embodiments the preferred transmembrane carrier compositions of the present invention contain less than about 2% w / w or less than 1%, less than 0.5% or even 0% viscosity-improving agents. For example, in several embodiments the compositions contain less than these amounts of the organic and inorganic salts, such as the salts of hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, carbonic acid, hydrobromic acid or hydroiodic acid. Also preferred compositions contain less than 2% w / w or less than 1% or even 0% potassium bromide, potassium chloride, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium sulfate, potassium iodide , potassium nitrate, lithium bromide, lithium chloride, lithium iodide, lithium nitrate, lithium sulfate, ammonium bromide, ammonium chloride, ammonium carbonate, ammonium hydrogen carbonate, ammonium dihydrogen phosphate, phosphate of diammonium hydrogen, ammonium iodide, ammonium nitrate, ammonium sulfate, ammonium bromide, sodium carbonate, sodium chloride, sodium hydrogen carbonate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium nitrate , sodium phosphate and sodium sulfate.

Other salts which are preferably present in the compositions of the transmembrane carrier in less than 2% w / w or less than 1% or even 0% alkanolamine chloride, sulfate, phosphate, benzoic acid, acetic acid, salicylic acid, phthalic acid of oxalic acid, gluconic acid, 1-naphthalenesulfonic acid, 2-naphthalenesulfonic acid, tartaric acid, maleic acid, malonic acid, succinic acid, fumaric acid, propionic acid, ascorbic acid, mandelic acid, malic acid, citric acid, chloride of triethianolammonium, triethanolammonium dihydrogen phosphate, triethianolammonium sulfate, sodium benzonate, potassium benzonate, ammonium benzonate, sodium acetate, potassium acetate, ammonium acetate, sodium salicylate, potassium salicylate, ammonium salicylate, oxalate of potassium, ammonium oxalate, sodium phthalate, potassium phthalate, ammonium phthalate, sodium gluconate, potassium gluconate, gluconato de amo child, ammonium 1-naphthalenesulfonate, potassium 2-naphthalenesulfonate, ammonium 2-naphthalenesulfonate, sodium 2-naphthalenesulfonate, potassium tartrate, sodium maleate, potassium maleate, sodium malonate, sodium succinate, sodium fumarate, sodium propionate, triethanolammonium propionate, sodium ascorbate, triethanolammonium ascorbate, potassium ascorbate, sodium mandelate, sodium malate, sodium citrate, potassium citrate and triethanolammonium citrate.

In various embodiments, the compositions of the transmembrane carrier useful in the invention have a viscosity of at least 10,000 centipoise or at least 20,000 centipoise, or at least 30,000 centipoise or at least 40,000 centipoise or at least 50,000 centipoise or at least 60,000 centipoise or at least 70,000 centipoises, all at 58 ° C, without the presence of any methyl cellulose or other viscosity improving agent. Because methylcellulose and other viscosity improving agents are not present in the formulations, the transmembrane penetration is substantially increased. In one embodiment, the oleyl alcohol can be added to improve the transmembrane penetration of the drug that is in the composition but is present outside the liposomes.

Without wishing to agree with any particular theory, it is believed that it is the combination of water-soluble preservative and the lipid-soluble antioxidant that provides stability to these particular liposomes. This allows the liposomes to be stable and also have a high viscosity. High viscosity is possible even though the composition of the transmembrane carrier contains little or no viscosity improving agent. It is believed that viscosity improving agents impair movement of the active compound through the skin. The present compositions offer the superior property of a maximum degree of penetration of the skin in the administration of the active ingredient while retaining a sufficient viscosity.

If the liposome is a vesicle-based phospholipid, a preferred lipid will be Phospholipon 90H, which is obtained and purified from soybean lecithin and has the chemical name 1, 2-dia-cial-5N-glycero-3-phosphatidyl choline. It is at least 90% phosphatidyl choline and is completely hydrogenated. But one skilled in the art will recognize that the other lipids can also be used in the present invention. For example, the phosphatidinylcholine may be of lower purity or may contain other lipids or carrier materials, such as, for example, propylene glycol / ethanol, medium chain triglycerides, ethanol / oil, phosphatidic acid, cholesterol and phosphatidylinositol. The phospholipid can be any natural or synthetic phospholipid, for example phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol, phosphatidic acid, lysophospholipids, soy or egg phospholipid or a combination of them. The phospholipid can be salted or desalted, hydrogenated or partially hydrogenated, natural, synthetic or semi-synthetic. Examples of commercially available phospholipids include but are not limited to egg phospholipids P123 (Pfanstiehl, Waukegen, IL), Lipoid E80 (Lipoid, Ludwigshafen, Germany) and the hydrogenated soy phospholipids Phospholipon 80H®, 80G®, 90H® and 100H ® (Nattermann, Munich, Germany) and 99% pure soy phosphatidyl choline (Avanti Polar Lipids, Alabster, AL).

Optionally, the dehydrated alcohol and propylene glycol can be used as co-solvents of the lipid phase and the vitamin E acetate can be included as an antioxidant. In various embodiments, other lipids or substances such as lipids are used in the invention, such as ceramides, lecithins, ethanolamines of phosphatidyl, phosphatidyl serines, cardiolipins, trilinoleines and the like compounds. The nonphospholipids can also be used in the present invention. For example, non-phospholipid materials that may be useful include polyoxyethylene fatty esters of lipid vesicle formation, polyoxyethylene fatty acid esters, diethanolamines, long chain acyl amines, polyoxyethylene sorbitan oleates, piolyoxyethylene glycerol monostearate, glycerol monostearate and mixtures, analogs and derivatives thereof. The vesicles may also include a steroid and a charge producing agent. Preferred steroids include cholesterol, hydrocortisone and the like, derivatives and mixtures thereof. Preferred negative charge producing materials are oleic acid, dicetyl phosphate, palmitic acid, cetyl sulfate, retinoic acid, phosphatidic acid, phosphatidyl serine and mixtures thereof. To provide a net positive charge for the vesicles when desired, the long chain amines, for example stearyl amines or oleyl amines, the long chain pyridinium compounds, i.e., pyridinium cetyl chloride, quaternary ammonium compounds or mixtures of these can be used, as long as the lipid vesicle can carry sufficient quantities of the aqueous phase.

Other liposomal formulations including non-phospholipid liposomes can be used in the invention. For general reference, the phase liposomal drug release system Multiple described in US Patent No. 4,761, 288, issued August 2, 1988 to Mezei (the description of which is incorporated herein by reference), is an exemplary representation of the liposome compositions that can be used in the invention. To be used as a transmembrane carrier, the modification of the liposome (or other lipid vesicle used in the invention) to sterically stabilize the vesicle or to provide the target or to provide the vesicle (or carrier lipid based on lipids used) with properties of Slow release may interfere with the transmembrane activity of the composition and is therefore not preferred.

Preferred transmembrane carrier compositions for use in the invention are "Stable" which means that they can be stored for at least 6 months, 1 year or 2 years are changing the chemical or physical properties of the composition.

There is no theoretical limit to the number of compounds that can be incorporated into a lipid-based carrier for use in the invention. However, as those skilled in the art are attentive, the encapsulation efficiency is generally greater in liposomal compositions having a relatively high lipid: water content and a lipid soluble drug carrier in a lipid phase can generally be provided in a higher concentration than the water soluble drug carried in an aqueous phase.

For example, two or more ingredients can be encapsulated in the same vesicle or if the active components are incompatible, the compounds can be separately encapsulated and the combined transmembrane carrier compositions provide a composition with two or more indications, or that treat a simple indication with compounds multiple assets.

It is also possible contemporarily to treat the middle ear and the auditory canal (i.e., to treat an infection in the anterior and reduce inflammation in the latter) by administering a composition of the transmembrane carrier that includes a first set of one or more active compounds for the treatment of the middle ear encapsulated in the vesicle and a second set of one or more active compounds for treating the auditory channel dispersed in the non-encapsulated form in a surrounding water phase. The first encapsulated set of compounds will cross the eardrum membrane in the middle ear, the second non-encapsulated set of compounds will not.

Co-administration can be achieved by, for example, administering the second set of compounds in a slow release form, such as in liposomes manufactured to resist degradation. Those skilled in the art will be familiar with manufacturing methods that meet this objective, including without limitation, the addition of cholesterol for the lipid phase (see, for example, US Patent No. 6,532,716 incorporated herein by reference as an illustration of a method for incorporating cholesterol into the liposomes at this term) and using agents for viscosity improvement (such as methylcellulose) during the manufacture of the liposome.

Said relatively insoluble lipid vesicles are less suitable for administration of drugs through the tympanic membrane but may instead be expected to remain where they are administered, to slowly release the medicament comprising the second set of compounds (or additional) in the ear canal (that is, to treat inflammation in it or provide a pain eliminator). Said vesicles may also have disinfecting properties or other properties useful in the treatment or control of the proportion of infection in the outer ear, ie, if trimethylammonium bromide, a potent disinfectant, is used as a material that produces positive charge within the vesicles provide a second advantage. In such modalities, the vesicles act as a germicidal sustained release carrier as each deteriorates.

C. Useful Medications for the Treatment and Prophylaxis of Otitis Media "Drug" means any biologically active compound useful in the treatment and / or prevention of middle ear infections and their sequelae, as well as associated pain and inflammation. In this regard, therefore, the particularly preferred medicaments are antibiotics useful in the treatment or prevention of middle ear infections in mammals, especially humans. Depending on the severity of the infection and its cause, such antibiotics include no limit, amoxicillin (and other penicillins), ciprofloxacin (and other quinolone antibiotics, such as oflixacin), clavulanate (and other beta-lactamase inhibitors), cefaclor), and others. cephalosporins, such as cefixime), azithromycin (and other macrolide antibiotics, such as clarithromycin) and sulfisoxazole (as well as other sulfa drugs, such as sulfamethoxazole). Of the antibiotics useful in the invention, ciprofloxacin is currently preferred.

Sulfisoxazole and amoxicillin are the main antibiotics that are also accepted for use in the prophylaxis of recurrent middle ear infections. Broad spectrum antibiotics such as amoxicillin and ciprofloxacin are especially preferred for use in the treatment of middle ear infections, especially in persons in whom an antibiotic resistant infection is suspected.

Anti-inflammatory compounds useful for co-administration or independent use of antibiotic therapy include those that are sometimes less effective or less well tolerated on oral administration, i.e. non-steroidal anti-inflammatory compounds, such as naproxen , ketoprofen, celecoxib and indomethacin. Anti-viral compounds such as acyclovir can be administered in place of, or as an adjunct to, antibiotic compounds when clinically indicated such as anti-fungal compositions. Other medicaments for use in the treatment and prevention of middle ear infections and their sequelae can also be administered by applying the compositions of the transmembrane carrier of the invention to the tympanic membrane.

In some embodiments, the compositions of the transmembrane carrier of the present invention contain more than one medicament. For example CLAMOXYL® and AUMENTIN® are both compositions of the combination agent for oral administration which are commonly prescribed for the treatment of otitis media. Each composition contains two active antibiotic ingredients, amoxicillin and clavulanate. The compositions of the transmembrane carrier provide such multiple agents that are particularly preferred for use in the appropriate indications.

EXAMPLE 1 EXAMPLING FORMULA A This section provides an example of the starting materials for the manufacture of a composition of the transmembrane carrier of the present invention containing ciprofloxacin. The composition of the transmembrane carrier comprises a liposome and contains the following ingredients in the percentages listed weight / weight. PHOSPHOLIPON® 90H 5.00 or less Alcohol, dehydrated, USP 5.00 or less Propylene glycol, USP 5.00 Vitamin E acetate 1.00 Benzethonium chloride 0.02 Ciprofloxacin 0.30 or as required to provide the therapeutic dose Purified water 76.98 or more.

EXAMPLE 2 MANUFACTURING EXAMPLES METHOD FOR FORMULATION A This section provides an example of how a composition of the transmembrane carrier of the present invention containing ciprofloxacin is made.

Aqueous phase. The process of preference is practiced using two vortex stainless steel hydration chambers with covers. In the larger of the two chambers, the purified water and the benzethonium chloride were combined slowly to avoid foaming or bubbles on the surface. Heat was applied to obtain 50 ° C ± 2 ° C, the white temperature of the aqueous phase. The chamber is covered to prevent water evaporation and is equipped with a lower port and valve to regulate the flow of material out of the vessel.

Phase Lipid. A second mixing vessel covered in stainless steel is used in close proximity to the first. In this secondary chamber, dehydrated alcohol and propylene glycol are first combined slowly to avoid foaming or bubbles on the surface. An upper mixer was started and heat was applied to obtain 58 ± 2 ° C with a target of 58 ° C. When the solution reached the white temperature, ciprofloxacin was added and completely dissolved. Subsequently PHOSPHOLIPON® 90H and vitamin E acetate were added and combined with the lipid phase until dissolved / mixed. A cover was used in the chamber to prevent evaporation of the alcohol through the process.

Hydration of the Lipida Phase. The values were opened in the lower ports of the chamber and the flow was regulated from both vessels. The aqueous phase and the oily phase flowed and were gathered in an on-line regulation tea and a dispersion pump pushed the two phases together. The mixture was circulated through a 60 mesh dispersion screen to optimize the hydration of the lipid phase. The mixture was then directed to the top of the chamber and the entire process was circulated through the pump, returning to the camera for 10 minutes.

Cooling phase. After circulation, the chamber cover was cooled with continuous slow mixing until the temperature of the product was 28 ° C, completing the process.

The combination of materials is preferably fast enough for complete mixing without causing foaming or bubbling. The process of preferably cooling is slow with cooling of about 6 ° C per hour more preferably.

EXAMPLE 3 USE OF EXEMPLARY FORMULATIONS FOR THE TREATMENT OF MEDIUM OTITIS To treat an infection in the middle ear and the sequelae thereof in an affected individual, a liposome containing the medicament according to the present invention is administered to the patient by transmembrane administration to the tympanic membrane. The medicament is one that is useful in the prophylaxis and / or treatment of middle ear infections and is an antibiotic, an antiviral agent or a pain-killing agent such as a non-steroidal anti-inflammatory agent.

Transmembrane administration is achieved by, for example, applying the composition of the transmembrane carrier of the invention to the tympanic membrane with a needleless syringe or other appropriate device for medical insertion into the ear canal. The administration is repeated as required to achieve the therapeutically effective dose level for the given antibiotic compound. The pain can be treated by administering in the same general manner the compositions of the transmembrane carrier containing anti-inflammatory and / or pain-relieving compounds of the composition.

Based on current protocols used to introduce antibiotics into the middle ear through the tympanic drainage tube in situ, an appropriate dose region with the exemplary formulation described in Example 1 would be 5 drops / twice a day for a child less than 12 years old and 10 drops / twice a day for a child 12 years of age or older.

Prophylactic treatment against recurrence of a middle ear infection can be provided in the same manner, using a composition of the transmembrane carrier of the invention which contains a prophylactically effective antibiotic or other medicament.

The invention which has been fully described, its practice is illustrated by the following examples. These examples are representative, not exhaustive, of the methods for practicing the invention and the results that can be obtained through them.

EXAMPLE 4 ANIMAL MODEL (CHINCHILLA) OF OTITIS MEDIA The chinchilla langer is ideally established as an animal species for the study of the efficacy of treatment for otitis media in humans. The chinchillas are small, have very similar hearing capabilities to humans, have a cochlea with membranous architecture similar to the human cochlea, do not manifest presbycusis in long-term studies and lack susceptibility to middle ear infections of natural occurrence, which are common for guinea pigs and rabbits. See, for example Hajek DM, Yuan Z, Quartey MK, Giebink GS., Otitis Media: The Chinchilla Model. in: Zak O, Sande M, editors, Handbook of Animal Models of Infection, San Diego CA: Academic Press (1999), on pages 389-403, the contents of which are incorporated herein by reference to illustrate nature and acceptance in the technique of this animal model.

To establish and evaluate the animal model, each chinchilla was inoculated with Haemophilus infiuenzae directly into the middle ear by transbular injection at a concentration of 100 cfu in a volume of 0.2 ml. Each chinchilla underwent an ear examination with an otoscope before being placed in the study. The dose with a composition of the invention or oral control amoxicillin started approximately 48 hours after the bacterial inoculation. All animals were administered with Burprenorphine 0.05 mg / kg twice daily subcutaneously for analgesia for the duration of the study.

At the end of the dose period (8 days after the bacterial inoculation), each animal was euthanized, its auditory canals were washed with saline solution and examined. In particular, samples from the middle ear of each chinchilla were collected. An auditory sample was grown overnight through laboratory procedures. Approximately 24 hours after the samples were plated, the colony forming units (cfu) were counted and recorded.

EXAMPLE 5 TREATMENT OF MEDIUM OTITIS IN THE CHINCHILLA MODEL (LIPOSOMAL LIPIDS) The positive control article (amoxicillin) was orally administered by forced feeding to three chinchillas twice a day for six days, approximately 8 hours later. 2, 4 or 6 drops of ofloxacin 0.3% of the liposome formulation were administered to two groups of three chinchillas each as a maximum feasible dose for these animals.

The results in each group (3 non-pregnant female animals / group) were as follows: Untreated animals: Active infection still present after 6 days. Control animals: Amoxicillin, 20 mg / kg BID for 6 days. No active infection present in any animal after 6 days. Animals treated in accordance with the methods of the invention: Ciprofloxacin, 4 drops BID for 6 days, No infection in any animal after 6 days.

Ofloxacin, 2 drops BID, 6 days. Active infection still present in two animals after 6 days, none present in the third animal.

Ofloxaxino, 4 drops BID, 6 days. Active infection still present in an animal after 6 days, none present in the other two animals.

EXAMPLE 6 TREATMENT OF MEDIUM OTITIS IN A CHINCHILLA MODEL (NON-LIPOSOMAL LIPIDS) Using the ciprofloxacin formulations in liposomes and non-liposomal lipids following the protocol described in Example 5, the following results were obtained: Number of infected ears Group Formulation Treatment / total number of ears None Not treated 7 of 10 Formulation of O of 10 Ciprofloxacin 2 (liposomal) O Formulation of 10 Ciprofloxacin 3 (Non-liposomal) These results demonstrate the efficiency of the present invention in the treatment of middle ear infection in a relevant animal model, with dose dependence in the treated animals.

The invention described illustratively in this document may be practiced in the absence of any element or elements, limitation or limitations that are not specifically described in this document. The terms and expressions that have been used are used as terms of description and not limitation and there is no intention that the use of such terms and expressions excludes any equivalent of the characteristics shown and described or portions thereof, but recognizes that several modifications are possible within the scope of the claimed invention. Furthermore, it should be understood that the present invention has been specifically described by the preferred embodiments and the additional features, the modification and variation of the concents described herein may be appealed by those skilled in the art and that said modifications and variations are considered within of the scope of this invention as defined by the appended claims.

The contents of the articles, patents and patent applications and all other documents and the electronically available information mentioned or cited in this document are incorporated therein as a reference in their entirety to the same extent as if each individual publication were specifically and individually indicated to be incorporated as reference. Applicants will reserve the right to physically incorporate into their application any and all materials and information of said articles, patents, patent applications or other documents.

The inventions described illustratively in this document may be properly practiced in the absence of any element or elements, limitation or limitations not specifically described in this document. In addition, for example, the terms "comprising", "including", "containing" etc. they should be read expansively and without limit.

Additionally, the terms and expressions used in this document have been used as terms of description and without limit and there is no intention in the use of such terms and expressions to exclude any equivalent of the characteristics shown and described or portions thereof, but recognizes that several modifications are possible within the scope of the claimed invention. Furthermore, it should be understood that while the present invention has been specifically described by the preferred embodiments and optional features, the modification and variation of the claimed inventions herein described may be appealed by those skilled in the art and that said modifications and variations are considered to be within the scope of this invention.

The invention has been described broadly and generically in this document. Each of the narrower species and subgeneric groups that fall within the generic description also form part of the invention. This includes the generic description of the invention with the provision or negative limitation that removes any subject matter of the genre, regardless of whether or not the material exercised is specifically mentioned in this document. Other embodiments are set forth within the following claims.

Furthermore, where the features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention also by means of this document is described in terms of any individual member or subgroup of members of the Markush group. .

Claims

1. A method for treating or preventing an infection in the middle ear and the sequelae thereof by transmembrane administration of a medicament thereto, said method comprising: applying a composition of the transmembrane carrier to the outer surface of the tympanic membrane, said composition of the transmembrane carrier comprising a medicament useful in the treatment or prevention of middle ear infections and the sequelae thereof.

2. A method for treating or preventing an infection in the middle ear and the sequelae thereof by transmembrane administration of a medicament thereto, said method comprising: applying a composition of the non-sterically stabilized transmembrane carrier to the outer surface of the tympanic membrane, said composition of the transmembrane carrier comprising a medicament useful in the treatment or prevention of middle ear infections and the sequelae thereof.

3. The method according to claim 1, wherein the transmembrane carrier is a lipid vesicle.

4. The method according to claim 2, wherein the non-sterically stabilized transmembrane carrier is selected from the group of lipid vesicles consisting of liposomes, micelles, lyosomes, niosomes and transfersomes.

5. The method according to claim 5, wherein the non-sterically stabilized transmembrane carrier is a liposome.

6. The method according to claim 1 or 2, wherein the composition of the transmembrane carrier is a liposome comprising: a water-soluble preservative and a lipid-soluble antioxidant; wherein at least 75% of the liposomes are from about 0.5 μm to about 10 μm in diameter and wherein said composition has a viscosity of at least 20,000 centipoise and contains less than 2% w / w of a growth enhancing agent. viscosity.

7. The method according to claim 1, wherein said medicament is an antibiotic.

8. The method according to claim 2, wherein said medicament is an antibiotic.

9. The method according to claim 8 or 9, wherein the antibiotic is selected from the group consisting of quinolone antibiotics, penicillin antibiotics, macrolide antibiotics, cephalosporin antibiotics, sulfa antibiotics and beta-lactamase inhibitors.

10. The method according to claim 8 or 9, wherein said antibiotic comprises ciprofloxacin and is administered to treat or prevent an infection of the middle ear.

11. The method according to claim 8 or 9, wherein said antibiotic comprises ofloxacin and is administered to treat or prevent an infection of the middle ear.

12. The method according to claim 8 or 9, wherein said antibiotic comprises sulfisoxazole and is administered to treat or prevent an infection of the middle ear.

13. The method according to claim 8 or 9, wherein said antibiotic comprises amoxicillin and is administered to treat or prevent an infection of the middle ear.

14. The method according to claim 8 or 9, wherein the antibiotic is provided in a concentration of 0.3% w / w of the composition.

15. The method according to claim 1, wherein said medicament is an anti-viral agent.

16. The method according to claim 2, wherein said medicament is an anti-viral agent.

17. The method according to claim 16 or 17, wherein the anti-viral agent is acyclovir.

18. The method according to claim 1 or 2, further comprising administering a medicament for treating pain, infection or inflammation in the outer ear.

19. The method according to claim 19, wherein the medicament for treating pain, infection or inflammation in the outer ear is provided in a sterically stabilized lipid vesicle.

20. The method according to claim 20, wherein the sterically stabilized lipid vesicle is a liposome.

21. The method according to claim 22, wherein the liposome is stabilized with cholesterol.

22. The method according to claim 19, wherein said medicament is selected from the group consisting of celecoxib, naproxen, indomethacin, ketoprofen, glucosamine, methylsulfonylmethane, pregnenolone, S-adenosylmethionne and combinations of any two or more thereof.

23. The method according to claim 20, wherein said medicament is selected from the group consisting of celecoxib, naproxen, indomethacin, ketoprofen, glucosamine, methylsulfonylmethane, pregnenolone, S-adenosylmethionne and combinations of any two or more thereof.

24. The method according to claim 1 or 2, wherein the composition of the transmembrane carrier is applied to the tympanic membrane during an acute phase of middle ear infection.